Although several novel therapeutic approaches have been developed for treatment of follicular lymphomas (FL), the overall survival has not yet been significantly improved. In vitro studies have provided evidence that FL cell survival is influenced by signals from the neoplastic microenvironment. FL cells associate with stromal elements known as follicular dendritic cells (FDCs), which provide anti-apoptotic signals to FL cells and chemotactic factors that likely contribute to the localization of FL cells within lymphoid follicles. Since FDCs provide survival and homing signals to lymphoma cells, targeting these cells in the microenvironment may be a novel treatment approach for FL. TNF( is overexpressed by FL cells, and TNF( upregulates the expression of adhesion molecules, cytokines and chemokines which are critical to FL cell-FDC interactions. Etanercept is a soluble, dimeric, recombinant human p75 TNFR, fused to the Fc fragment of human IgG1, developed for neutralization of TNF( and is an approved therapy for rheumatoid arthritis with an favorable toxicity profile. We hypothesize that TNF( blockade will affect the tumor microenvironment and therefore alter FL celI-FDC interactions, and FL cell survival. To investigate this hypothesis we propose three specific aims. First, to undertake a clinical trial of etanercept for patients with relapsed FL. Second, to investigate effects of etanercept on the tumor microenvironment directly and indirectly through studies of surrogate markers. We will investigate effects on FDCs, surrogate peripheral blood and serum markers as well as utilize PET scanning to assess the potential biologic activity of etanercept. Third, to investigate the effects of etanercept on T cell activation. Since TNF( is important in T cell function, it will be important to understand the effects of etanercept on T cells in these patients. This study is a novel approach to treating FL, where targeting the microenvironment of the tumor may inhibit the growth and survival of the neoplastic cells.